title: Intrathecal injection of the sigma(1) receptor antagonist BD1047 blocks both mechanical allodynia and increases in spinal NR1 expression during the induction phase of rodent neuropathic pain.
abstract: BACKGROUND
  Selective blockade of spinal sigma(1) receptors (Sig-1R) suppresses nociceptive behaviors in the mouse formalin test. The current study was designed to verify whether intrathecal Sig-1R antagonists can also suppress chronic neuropathic pain.
  
  
  METHODS
  Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. The Sig-1R antagonist BD1047 was administered intrathecally twice daily from postoperative days 0 to 5 (induction phase of neuropathic pain) or from days 15 to 20 (maintenance phase). Western blot and immunohistochemistry were performed to determine changes in Sig-1R expression and to examine the effect of BD1047 on N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation in spinal cord dorsal horn from neuropathic rats.
  
  
  RESULTS
  BD1047 administered on postoperative days 0-5 significantly attenuated CCI-induced mechanical allodynia, but not thermal hyperalgesia, and this suppression was blocked by intrathecal administration of the Sig-1R agonist PRE084. In contrast, BD1047 treatment during the maintenance phase of neuropathic pain had no effect on mechanical allodynia. Sig-1R expression significantly increased in the ipsilateral spinal cord dorsal horn from days 1 to 3 after CCI. Importantly, BD1047 (30 nmol) administered intrathecally during the induction, but not the maintenance phase, blocked the CCI-induced increase in N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation.
  
  
  CONCLUSIONS
  These results demonstrate that spinal Sig-1Rs play a critical role in both the induction of mechanical allodynia and the activation of spinal N-methyl-d-aspartate receptors in CCI rats and suggest a potential therapeutic role for the use of Sig-1R antagonists in the clinical management of neuropathic pain.
authors.affiliation: College of Veterinary Medicine and BK21 Program for Veterinary Science, Seoul National University, Seoul, Republic of Korea.
authors.forename: Dae-Hyun
authors.initials: DH
authors.lastname: Roh
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Kim
authors.forename: Seo-Yeon
authors.initials: SY
authors.lastname: Yoon
authors.forename: Hyoung-Sig
authors.initials: HS
authors.lastname: Seo
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Kwon
authors.forename: Kee-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Ho-Jae
authors.initials: HJ
authors.lastname: Han
authors.forename: Alvin J
authors.initials: AJ
authors.lastname: Beitz
authors.forename: Heung-Sik
authors.initials: HS
authors.lastname: Na
authors.forename: Jang-Hern
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D005029:Ethylenediamines / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007278:Injections, Spinal; D008297:Male; D009437:Neuralgia / Q000378:metabolism* / Q000517:prevention & control*; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
chemical_list: D005029:Ethylenediamines; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin